Live, attenuated vital vaccines are among the most successful means of controlling vital disease. However, for some virus pathogens, immunization with a live virus strain may be either impractical or unsafe. One alternative strategy is the insertion of genes encoding immunizing antigens of such agents into the vaccine strain of another virus. However, relatively few such systems are currently available.
Hahn et al., Proc. Natl. Acad. Sci. USA 89, 2679 (1992), describes Sindbis virus constructs which express a truncated form of the influenza hemagglutinin protein. The constructs are used to study antigen processing and presentation in vitro and in mice. Although no infectious challenge dose is tested, it is also suggested that such constructs might be used to produce protective B- and T-cell mediated immunity. The final paragraph of the discussion section states: "Although SIN is not likely to be approved for use as a human vaccine, a parallel approach to the one used here for SIN may be applicable for developing live-attenuated vaccine strains using viruses with similar replication strategies, such as attenuated strains of Venezuelan equine encephalitis virus . . . (citing Davis et al.)" Insofar as applicant is aware, a problem with the Sindbis vector is that the heterologous insert is unstable therein and is "kicked out" of the vector, with the practical limit for stable inserts being about 1 kb.
Davis et al., U.S. Pat. No. 5,185,440, describes cDNAs encoding the VEE virus and attenuated mutations which may be incorporated therein for use in making a vaccine. The use of a subgenomic expression system is neither suggested nor disclosed.